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1.
Morfologiia ; 116(6): 19-22, 1999.
Artigo em Russo | MEDLINE | ID: mdl-10709193

RESUMO

Changes of neurons of dorsal motor nucleus of nervus vagus were studied in adaptation to hypoxia, experimental diabetes mellitus and its correction by means of interrupted hypoxic effects. It was established previously that interrupted hypoxic training exerted stimulating effect on insulin synthesizing function of pancreas. As a result of the present study the increase of morphofunctional activity of neurons was found in all experimental series although it was greater manifested in animals with experimental diabetes mellitus who were subjected to actions of hypoxia. The changes of morphofunctional activity of dorsal motor nucleus of nervus vagus established allow to conclude on the significant role these structure plays in realization of stimulating effect of interrupted actions of hypoxia on the state of insulin synthesizing function of pancreas and clinical characteristics of the experimental diabetes mellitus.


Assuntos
Diabetes Mellitus Experimental/fisiopatologia , Hipóxia Encefálica/fisiopatologia , Neurônios/patologia , Nervo Vago/fisiopatologia , Adaptação Fisiológica , Animais , Câmaras de Exposição Atmosférica , Carbutamida , Diabetes Mellitus Experimental/etiologia , Hipoglicemiantes , Masculino , Neurônios/fisiologia , Ratos , Ratos Wistar , Fatores de Tempo
2.
Exp Clin Endocrinol Diabetes ; 106(2): 149-51, 1998.
Artigo em Inglês | MEDLINE | ID: mdl-9628248

RESUMO

This work describes the history of the first oral antidiabetic in East and West Germany. M. Janbon and A. Loubatières reported experimental and clinical findings about a blood sugar-decreasing effect of a sulphonamide derivate, sulphoisopropyl thiodiazol (1942). These findings, however, did not prove to be useful in the treatment of diabetes. In 1952 the author found a series of hypoglycemic shocks with the sulfonamid-urea derivate carbutamdide during clinical tests of infectious diseases. These were reported to the pharmaceutical company Von Heyden in Dresden. The head chemist E. Haack went with my files from East to West Germany, to Boehringer Mannheim. Without mentioning the synthesis in Dresden, he synthesized carbutamide in Mannheim. The hypoglycemic effect was rediscovered by his friend H. Franke together with J. Fuchs. It took twenty years until the results of the author's research were officially acknowledged.


Assuntos
Carbutamida/história , Hipoglicemiantes/história , Administração Oral , Carbutamida/uso terapêutico , Diabetes Mellitus/tratamento farmacológico , Alemanha , História do Século XX , Humanos , Hipoglicemiantes/uso terapêutico
3.
Br J Pharmacol ; 123(6): 1023-30, 1998 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-9559882

RESUMO

1. The structure activity relationships for the insulin secretagogues N-benzoyl-D-phenylalanine (NBDP) and related compounds were examined at the sulphonylurea receptor level by use of cultured HIT-T15 and mouse pancreatic beta-cells. The affinities of these compounds for the sulphonylurea receptor were compared with their potencies for K(ATP)-channel inhibition. In addition, the effects of cytosolic nucleotides on K(ATP)-channel inhibition by NBDP were investigated. 2. NBDP displayed a dissociation constant for binding to the sulphonylurea receptor (K(D) value) of 11 microM and half-maximally effective concentrations of K(ATP)-channel inhibition (EC50 values) between 2 and 4 microM (in the absence of cytosolic nucleotides or presence of 0.1 mM GDP or 1 mM ADP). 3. In the absence of cytosolic nucleotides or presence of GDP (0.1 mM) maximally effective concentrations of NBDP (0.1-1 mM) reduced K(ATP)-channel activity to 47% and 44% of control, respectively. In the presence of ADP (1 mM), K(ATP)-channel activity was completely suppressed by 0.1 mM NBDP. 4. The L-isomer of N-benzoyl-phenylalanine displayed a 20 fold lower affinity and an 80 fold lower potency than the D-isomer. 5. Introduction of a p-nitro substituent in the D-phenylalanine moiety of NBDP did not decrease lipophilicity but lowered affinity and potency by more than 30 fold. 6. Introduction of a p-amino substituent in the D-phenylalanine moiety of NBDP (N-benzoyl-p-amino-D-phenylalanine, NBADP) reduced lipophilicity and lowered affinity and potency by about 10 fold. This loss of affinity and potency was compensated for by formation of the phenylpropionic acid derivative of NBADP. A similar difference in affinity was observed for the sulphonylurea carbutamide and its phenylpropionic acid derivative. 7. Replacing the benzene ring in the D-phenylalanine moiety of NBDP by a cyclohexyl ring increased lipophilicity, and the K(D) and EC50 values were slightly lower than for NBDP. Exchange of both benzene rings in NBDP by cyclohexyl rings further increased lipophilicity without altering affinity and potency. 8. This study shows that N-acylphenylalanines interact with the sulphonylurea receptor of pancreatic beta-cells in a stereospecific manner. Their potency depends on lipophilic but not aromatic properties of their benzene rings. As observed for sulphonylureas, interaction of N-acylphenylalanines with the sulphonylurea receptor does not induce complete inhibition of K(ATP)-channel activity in the absence of inhibitory cytosolic nucleotides.


Assuntos
Transportadores de Cassetes de Ligação de ATP , Ilhotas Pancreáticas/metabolismo , Fenilalanina/análogos & derivados , Canais de Potássio Corretores do Fluxo de Internalização , Canais de Potássio/metabolismo , Receptores de Droga/metabolismo , Trifosfato de Adenosina/metabolismo , Animais , Cálcio/metabolismo , Carbutamida/análogos & derivados , Carbutamida/farmacologia , Linhagem Celular Transformada , Cricetinae , Cicloexanos/farmacologia , Glibureto/metabolismo , Guanosina Difosfato/metabolismo , Ilhotas Pancreáticas/citologia , Ilhotas Pancreáticas/efeitos dos fármacos , Masculino , Camundongos , Nateglinida , Fenilalanina/metabolismo , Fenilalanina/farmacologia , Canais de Potássio/efeitos dos fármacos , Receptores de Sulfonilureias , Trítio
4.
J Biochem ; 121(4): 705-10, 1997 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-9163521

RESUMO

The structural requirements of acetohexamide reductases purified from rabbit liver, kidney, and heart for substrates and inhibitors were examined. Acetohexamide, an oral antidiabetic drug with a ketone group, and analogs of it with various alkyl groups instead of the cyclohexyl group were used as substrates for these three enzymes. The results obtained as to substrate specificity suggested that the nature of the substrate-binding region of the heart enzyme is markedly different from those of the substrate-binding regions of the liver and kidney enzymes. Tolbutamide, which has no ketone group within its chemical structure, strongly inhibited the heart enzyme, whereas it had little ability to inhibit the liver or kidney enzyme. The inhibition of the heart enzyme by tolbutamide was competitive with respect to acetohexamide and uncompetitive with respect to NADPH. Furthermore, tolbutamide analogs with n-pentyl and n-hexyl groups instead of the n-butyl group exhibited very pronounced inhibition of only the heart enzyme. Therefore, it is reasonable to postulate that the heart enzyme, unlike the liver and kidney ones, has a cleft of a strongly hydrophobic nature near its substrate-binding region, and that this hydrophobic cleft plays a critical role in the interaction of the heart enzyme with the cyclohexyl group of acetohexamide.


Assuntos
Oxirredutases do Álcool/antagonistas & inibidores , Oxirredutases do Álcool/metabolismo , Rim/enzimologia , Fígado/enzimologia , Miocárdio/enzimologia , Acetoexamida/análogos & derivados , Acetoexamida/química , Acetoexamida/metabolismo , Animais , Sítios de Ligação , Carbutamida/química , Carbutamida/farmacologia , Clorpropamida/química , Clorpropamida/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/metabolismo , Inibidores Enzimáticos/farmacologia , Hipoglicemiantes/farmacologia , Cinética , Oxirredução , Coelhos , Relação Estrutura-Atividade , Especificidade por Substrato , Tolbutamida/análogos & derivados , Tolbutamida/metabolismo , Tolbutamida/farmacologia , Triazinas/química , Triazinas/metabolismo , Triazinas/farmacologia
5.
Photodermatol Photoimmunol Photomed ; 12(4): 166-70, 1996 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-9017793

RESUMO

The sulphonamide-derived oral antidiabetic drugs carbutamide, chlorpropamide, glibenclamide, glibornuride, gliclazide, glipizide, gliquidone, glisoxepide, glymidine, tolazamide and tolbutamide were investigated for photohemolytic properties in vitro. Irradiation with a SOL 3 apparatus (solar simulating irradiation) revealed hemolysis in the presence of chlorpropamide, glipizide, gliquidone, glymidine and tolbutamide (all in the concentration 10(-3) mol/l). Except for glymidine, which exerted photohemolysis in the concentration 10(-4) mol/l, no hemolytic effects were seen in the concentration of 10(-4) mol/l or 10(-5) mol/l. Irradiation with TL 12 light bulbs (UVB), a UVASUN 5000 apparatus (UVA) or an experimental lamp (visible light) did not induce phototoxic hemolysis with either of the test substances. Addition of the antioxidants ascorbic acid, alpha-tocopherol or superoxide dismutase significantly inhibited the phototoxic hemolysis. Investigations carried out in a nitrogen-rich atmosphere reduced the hemolysis as well. These findings indicate an involvement of reactive oxygen species in the mechanism of action of the hemolytic process in the presence of oral antidiabetic drugs.


Assuntos
Antioxidantes/farmacologia , Hemólise/efeitos da radiação , Hipoglicemiantes/efeitos adversos , Nitrogênio/farmacologia , Radiossensibilizantes/efeitos adversos , Sulfonamidas/efeitos adversos , Antioxidantes/administração & dosagem , Ácido Ascórbico/administração & dosagem , Ácido Ascórbico/farmacologia , Carbutamida/administração & dosagem , Carbutamida/efeitos adversos , Clorpropamida/administração & dosagem , Clorpropamida/efeitos adversos , Relação Dose-Resposta a Droga , Gliclazida/administração & dosagem , Gliclazida/efeitos adversos , Glipizida/administração & dosagem , Glipizida/efeitos adversos , Glibureto/administração & dosagem , Glibureto/efeitos adversos , Hemólise/efeitos dos fármacos , Humanos , Hipoglicemiantes/administração & dosagem , Nitrogênio/administração & dosagem , Radiossensibilizantes/administração & dosagem , Espécies Reativas de Oxigênio/fisiologia , Sulfonamidas/administração & dosagem , Compostos de Sulfonilureia/administração & dosagem , Compostos de Sulfonilureia/efeitos adversos , Superóxido Dismutase/administração & dosagem , Superóxido Dismutase/farmacologia , Tolazamida/administração & dosagem , Tolazamida/efeitos adversos , Tolbutamida/administração & dosagem , Tolbutamida/efeitos adversos , Raios Ultravioleta/efeitos adversos , Vitamina E/administração & dosagem , Vitamina E/farmacologia
7.
Diabetes Res Clin Pract ; 8(2): 109-14, 1990 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-2106423

RESUMO

The effects of first and second generation hypoglycemic sulfonylureas on the incidence of ventricular ectopic beats and on the duration of transitional ventricular fibrillation in the ischemic rat heart were investigated. First generation sulfonylurea compounds (tolbutamide, carbutamide and gliclazide) in 105 preparations increased, while second generation sulfonylurea compounds (glibenclamide and glipizide) in 50 preparations decreased in a dose-dependent manner both the number of ventricular ectopic beats and the duration of transitional ventricular fibrillation during the first 30 min after ligation of the left anterior descending coronary artery. Therefore, second generation sulfonylureas should be preferred in the treatment of type 2 diabetics with ischemic heart diseases, if satisfactory metabolic control cannot be achieved by a treatment regimen and diet alone.


Assuntos
Eletrocardiografia/efeitos dos fármacos , Hipoglicemiantes/farmacologia , Animais , Arritmias Cardíacas/fisiopatologia , Glicemia/metabolismo , Carbutamida/farmacologia , Relação Dose-Resposta a Droga , Gliclazida/farmacologia , Glipizida/farmacologia , Glibureto/farmacologia , Masculino , Infarto do Miocárdio/fisiopatologia , Potássio/sangue , Ratos , Ratos Endogâmicos , Valores de Referência , Relação Estrutura-Atividade , Tolbutamida/farmacologia
9.
Pharmazie ; 41(10): 717-9, 1986 Oct.
Artigo em Alemão | MEDLINE | ID: mdl-3823115

RESUMO

Dissociating drugs diffuse from saturated solutions with suspended drug particles across lipophilic membranes according to zero order kinetics. The highest rate is maintained even if large fractions of the drug are dissociated due to the pH-conditions of the solution. The pH range of the highest and pH-independent membrane transport corresponds with drug solubility/pH-profiles, showing the solubility of the undissociated drug.


Assuntos
Preparações Farmacêuticas/análise , Carbutamida/análise , Química Farmacêutica , Difusão , Dimetideno/análise , Concentração de Íons de Hidrogênio , Cinética , Membranas Artificiais , Solubilidade , Soluções
10.
J Infect Dis ; 153(5): 944-7, 1986 May.
Artigo em Inglês | MEDLINE | ID: mdl-3486236

RESUMO

Two sulfonylurea compounds, carbutamide and tolbutamide, were studied for efficacy against Pneumocystis carinii pneumonitis in the corticosteroid-treated rat model and compared with trimethoprim-sulfamethoxazole (TMP-SMZ). The chemical structures of these sulfonylureas are identical except that an amino group in carbutamide is replaced with a methyl group in tolbutamide. Carbutamide was totally effective in the prevention and treatment of P. carinii pneumonitis in dosages of 100 and 200 mg/kg per day. The carbutamide dosage of 50 mg/kg per day prevented the infection in 90% of animals, whereas tolbutamide in the same dosage permitted infection in 100% of animals. This study shows that carbutamide is at least as effective as TMP-SMZ in the treatment and prevention of murine P. carinii pneumonitis. The presence of an amino group in the para position on the benezene ring is a determinant for this activity.


Assuntos
Carbutamida/uso terapêutico , Pneumonia por Pneumocystis/tratamento farmacológico , Tolbutamida/uso terapêutico , Administração Oral , Animais , Anti-Infecciosos/uso terapêutico , Carbutamida/administração & dosagem , Fenômenos Químicos , Química , Combinação de Medicamentos/uso terapêutico , Tolerância Imunológica , Pneumonia por Pneumocystis/prevenção & controle , Ratos , Sulfametoxazol/uso terapêutico , Tolbutamida/administração & dosagem , Trimetoprima/uso terapêutico , Combinação Trimetoprima e Sulfametoxazol
12.
Eur J Clin Pharmacol ; 28(4): 367-70, 1985.
Artigo em Inglês | MEDLINE | ID: mdl-3928386

RESUMO

In diabetic patients it has been shown that tolbutamide and carbutamide enhanced and glibenclamide did not influence the incidence of digitalis intoxication, or that of multifocal ectopic beats or coupling due to premature ectopic ventricular beats during digitalis therapy. In rabbits glibenclamide decreased and tolbutamide and carbutamide increased strophanthidin toxicity in a dose dependent manner. It was concluded that glibenclamide should be preferred to tolbutamide or carbutamide in digitalis-treated diabetics, when satisfactorily metabolic control is not achieved with a dietary regime alone.


Assuntos
Glicosídeos Cardíacos/toxicidade , Coração/efeitos dos fármacos , Hipoglicemiantes/toxicidade , Idoso , Animais , Carbutamida/toxicidade , Relação Dose-Resposta a Droga , Feminino , Glibureto/toxicidade , Humanos , Masculino , Pessoa de Meia-Idade , Coelhos , Tolbutamida/toxicidade
13.
Acta Endocrinol (Copenh) ; 105(3): 385-90, 1984 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-6230850

RESUMO

Six hypoglycaemic sulphonylurea compounds were compared with regard to their ability to bind to beta-cell-rich pancreatic islets microdissected from ob/ob-mice. Glibenclamide differed from carbutamide, tolbutamide, chlorpropamide, glibornuride and glipizide in not being rapidly bound to an equilibrium, but accumulating progressively in amounts far exceeding the water space. An inhibitor of the anion channels in the beta-cell membrane, 4-acetamido-4'-isothiocyanate-stilbene-2,2'-disulphonic acid (SITS), suppressed the islet uptake of glibenclamide and to some extent also that of carbutamide and glibornuride. The unusual uptake characteristics of glibenclamide had their counterpart in a retardation of its maximal action in promoting the entry of Ca2+ into the beta-cells.


Assuntos
Glibureto/metabolismo , Ilhotas Pancreáticas/metabolismo , Compostos de Sulfonilureia/metabolismo , Animais , Carbutamida/metabolismo , Clorpropamida/metabolismo , Glipizida/metabolismo , Camundongos , Camundongos Obesos , Tolbutamida/metabolismo
17.
Farmakol Toksikol ; 46(4): 79-82, 1983.
Artigo em Russo | MEDLINE | ID: mdl-6617840

RESUMO

Experiments on animals were made to study the diabetogenous effect of repeated administrations of bucarban. The drug-induced immunization and insulin release were accompanied by the increased immune response of the humoral and cellular types specific for bucarban and insulin as well. The changes in the animals' immune status were accompanied by disorders of carbohydrate and lipid metabolism, characteristic for diabetes mellitus and by a lowering of the hypoglycemic effect of the antidiabetic drug in question. It was shown for the first time that the changes in carbohydrate, lipid and lipoprotein blood indicators seen in the animals given sulfanilamide antidiabetics occur in the presence of intense autoimmune response to the body own insulin and are undoubtedly related to this response.


Assuntos
Doenças Autoimunes/induzido quimicamente , Carbutamida/imunologia , Diabetes Mellitus Experimental/imunologia , Hipoglicemiantes/imunologia , Animais , Formação de Anticorpos/efeitos dos fármacos , Autoanticorpos/análise , Doenças Autoimunes/imunologia , Glicemia/análise , Diabetes Mellitus Experimental/etiologia , Adjuvante de Freund/administração & dosagem , Hipoglicemiantes/farmacologia , Imunidade Celular/efeitos dos fármacos , Imunização , Anticorpos Anti-Insulina/análise , Coelhos , Ratos , Fatores de Tempo
18.
Probl Endokrinol (Mosk) ; 29(1): 3-7, 1983.
Artigo em Russo | MEDLINE | ID: mdl-6340092

RESUMO

Critical analysis of studies, realized by the University Group on diabetes mellitus program (UGDP), involving 12 colleges of the USA, was performed. A higher death rate due to cardiovascular pathology was manifested by patients with diabetes mellitus given tolbutamide. A possible restriction and/or prohibition of drugs of this series was discussed. The literature data and the authors' findings are presented, disproving the results, obtained by this Group. A wide use of sulfanilurea derivatives is recommended in the treatment of early stages of the disease, provided a stable 24 hours' normoglycemia is attained in patients with evident diabetes. The results obtained and the literature data allow the conclusion, that sulfanilurea derivatives exert an antiatherogenic effect under conditions of diabetes mellitus compensation.


Assuntos
Carbutamida/uso terapêutico , Diabetes Mellitus/tratamento farmacológico , Estado Pré-Diabético/tratamento farmacológico , Tolbutamida/uso terapêutico , Ensaios Clínicos como Assunto , Diabetes Mellitus/sangue , Feminino , Humanos , Hipoglicemia/tratamento farmacológico , Masculino , Estado Pré-Diabético/sangue
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